Differences in the ability of human immunodeficiency virus type 1 (HIV-1) isolates and strains to infect different CD4+ T-cell types have been noted for several years. These differences, in some cases, have been correlated with AIDS presentation and/or progression. There have been only limited systematic studies to date investigating the basis for differences in CD4+ T-cell tropism. The major limitation to such studies has been the lack of availability of molecularly clones isolates having different phenotypes for comparative studies. We have molecularly cloned an isolate of HIV-1, termed HIV-1JR-CSF, which is completely restricted in its ability to productively infect CD4+ T-cell lines such as Jurkat, CEM, A3.01, HPB-ALL, and HUT 78 in vitro, but maintains the ability to infect primary peripheral blood T-cells efficiently. Initial studies suggest that this restriction is a function of viral entry processes, and indicate that the presence of CD4 is not sufficient for viral infection. The studies proposed in this application further investigate the molecular basis for the differences in tropism between HIV-1JR-CSF and other isolates of HIV. An understanding of restricted infection for CD4+ T-cells may provide therapeutic leads to block HIV infection at the same level of restriction. The Specific Aims are: 1. To determine the genetic basis for the inability of HIV-1JR-CSF to infect CD4+ T-cell lines. 2. To investigate the biochemical basis of HIV-1 CD4+ T-cell tropism, initially investigating the role of the env gene in HIV-1JR-CSF infection. 3. To investigate the basis for differences in susceptibility of cells to infection by HIV-1.